Non-medical use and abuse of prescription opiates is rising so that its prevalence is greater than that of heroin or cocaine abuse. In military and VA settings, soldiers and Veterans face acute or chronic pain that is managed by opiate narcotics and misuse of these agents is widely reported. Behavioral therapies and opiate substitution treatment for opiate addiction are time-intensive approaches that are incompletely effective and often inaccessible. During drug-taking, individuals are exposed to environmental cues or contexts where drugs of abuse are administered. The development of strong drug cue or contextual preferences accelerates the transition from intermittent drug use to drug addiction. Future exposure to these same cues elicits conditioned seeking behaviors and relapse via associative learning processes. This proposal examines the neurobiological mechanisms and treatment approaches to enhance the extinction of these conditioned drug responses. Our proposed preclinical research examines mechanisms of conditioned opiate reward (COR) and its extinction and tests novel pharmacological and behavioral extinction learning approaches in C57BL/6 mice. Previous research has shown that repeated opiate administration alters synaptic plasticity in cortical and limbic regions which underlie addiction-related behaviors. We hypothesize that repeated conditioning with morphine produces COR that is mediated by plasticity in motivational and cognitive neural circuits. We have established a model of opiate-induced conditioned place preference (CPP) in which cue and contextual preferences can be measured and then extinguished by repeated contextual exposure in a drug-free environment. We hypothesize that the extinction of COR is a new learning process that results in a decrease in the frequency or intensity of learned responses. COR is hypothesized to involve increases in brain derived neurotrophic factor (BDNF) in mesocorticolimbic dopamine neurons such as prefrontal cortex (PFC) and basolateral amygdala (BLA). Plasticity in opiate addiction is proposed to relate to BDNF's ability to increase protein synthesis in dendritic spines, alter connectivity and regulate long-term memory in COR extinction. We hypothesize that infusion of BDNF in PFC regions enhances the extinction of CPP and blocks priming-induced reinstatement of COR. We hypothesize that other pharmacological approaches which enhance BDNF plasticity also increase the rate and/or extent of extinction and reduce priming-induced reinstatement of CPP. Our studies use histone deacetylase inhibitor (HDACi) treatment for enhancing BDNF plasticity, extinguishing COR, and reducing priming-induced reacquisition of COR. Our aims will examine the BDNF and neurotrophic tyrosine kinase receptor (TrkB) receptor mechanisms in mesolimbic dopamine and prefrontal cortical neurons during COR and its extinction. We propose to examine the treatment effects of prefrontal cortical BDNF/TrkB signaling on the extinction of CPP and its priming- induced reinstatement of COR. Finally, we propose to examine the treatment effects of epigenetic regulation of BDNF using clinically available HDACi's, sodium butyrate and valproate, on the extinction and priming-induced reinstatement of COR. This translational research can directly advance new pharmacological and behavioral approaches to extinguish drug cue and contextual reactivity in addiction and can inform the design of clinical trials for opiate abusing Veterans. PUBLIC HEALTH RELEVANCE: Significance- Substance use is an enormous societal problem affecting 21 million persons in the US. The largest increase in recent drug abuse incidence is in the nonmedical use of opiate pain relievers (2.2 million persons). Access to new and effective therapeutic approaches for the millions of Americans who misuse opiate narcotics is desperately needed. The development of new non-addictive pharmacotherapeutic treatment regiments can augment cue exposure, motivational and cognitive psychotherapeutic approaches. Relevance to Veterans Health- Misuse of opiate pain relievers is a large concern in the VA. Nearly half of OEF/OIF veterans experience ongoing or new pain after service. Veterans with pain are prescribed opiate pain relievers and are at risk for their misuse. This proposal examines new treatment approaches using pharmacological and behavioral treatments to extinguish cue reactivity in an animal model. Such approaches can inform future clinical trials for opiate abusing veterans.